The renin-angiotensin system is one of the primary regulatory mechanisms for blood pressure in humans. Two drugs which act on the renin-angiotensin system are captopril and enalapril which are angiotensin converting enzyme (ACE) inhibitors. See Ondetti, M. et al., Science 1977, 196, 441; Ondetti, M. et al., J. Med. Chem. 1981, 24, 355 and Patchette, A. et al., Nature, 1980, 288, 280. A potentially more selective site for inhibition would be at the angiotensin II receptor as discussed by Duncia, J. et al., J. Med. Chem., 1990, 33, 1312; Carini; D. et al., J. Med. Chem., 1990, 33, 1330; Carini, D. and Duncia, J., Eur. Pat. Appl. 0253310 (Jan. 20, 1988); Johnson, A. et al., Drug News and Perspectives, 1990, 3, (6), 337; Chang, L., et al., European Patent Application No. 0412594A, (Jul. 23, 1990); Naka, T., et al., JP 200963 (filed Jul. 27, 1990) and Roberts, D. et al., GB 18402 (filed Aug. 10, 1990).
Most of the compounds reported recently as angiotension II receptor antagonists have the (2'-tetrazol-5-yl)biphenyl-4-yl)methyl moiety attached to a heterocycle (HET) represented by the following formula II: ##STR2##
See Johnson, A., et al., Drug News and Perspectives, 1990, 3, (6), 337; Naka, T., et al., JP 200963 (filed Jul. 27, 1990); Roberts, D. et al., GB 18402 (filed Aug. 10, 1990). chakravaty, P. K. et al, Eur. Pat. 0400974A (May 30, 1990); OKV, t, Setoi, H., Kayakiri, H., Inoue, I. and Kuroda, A., Eur. Pat. 0426021A (Oct., 26, 1990); Roberts, D. A., et al., Eur. Pat. 0425921A (May 18, 1990); Naka, T. and Nishikawa, K., Eur. Pat. 0425921A (Oct. 19, 1990) and Herold, P. and Buhlmayer, P., Eur. Pat. 0424317A (Oct. 10, 1990).
The preparation of compounds of the formula II starts with the intermediate 5-(4'-methyl[1,1'-biphenyl]-2-yl)-1H-tetrazole of the formula III: ##STR3## which is prepared from the nitrile of the formula IV: ##STR4## The conversion of the compound of formula IV to the compound of formula III is a process which requires the use of either highly toxic tin reagents (e.g. Bu.sub.3 SnN.sub.3) or the production of triphenylphosphine oxide and acrylonitrile. See, Aldrich, P. E., et al., U.S. Pat. No. 4,870,186 (Nov. 23, 1988); Aldrich, P. E., et al., U.S. Pat. No. 4,874,867 (Nov. 23, 1988); Aldrich, P. E., et al., Eur. Pat. 0291969 (May 19, 1988); Chakravarty, P. K., et al., Eur. Pat. 0401030A (May 31, 1990); Duncia, J. V., Pierce, M. E. and Santella, J. B. III, J. Org. Chem., 1991, 56, 2395; George, E. F. and Riddell, W. D., U.S. Pat. No. 3,865,570 (Feb. 13, 1973) and Herbst, R. M. and Wilson, K. R., J. Org. Chem., 1957, 22, 1142.
The preparation of certain biphenyl compounds has been reported when one reacts a Grignard reagent with a fluorobenzene which has a bis-oxazoline moiety. See, Cram, D. J., Katz, H. E. and Dicker, I. B., J. Am. Chem. Soc., 1984, 106, 4987 and Meyers, A. I. and Williams, B. E., Tetrahedron Lett., 1978, 223. Such compounds are, however, quite different from the compounds of formula III and those of the present invention.
It is an object of the present invention to develop a process for the preparation of compounds of the type represented by formula III which avoid the use or generation of highly toxic materials.